6. PROJECT SUMMARY The long-term objective of this proposal is to understand how genes specify the development and functioning of a behavioral system. Toward this end, the anatomically simple egg-laying system of the nematode Caenorhabditis elegans will be analyzed using methods of genetics, molecular biology, biochemistry, cell biology, electrophysiology and behavioral biology. Mutants abnormal in the development of the vulva (through which eggs are laid) will be studied to reveal the normal biological functions of and interactions among genes with human counterparts involved in cancer and other diseases. Because these genes act in different cell types, these studies might help reveal how cancer-gene mutations in one tissue lead to the cancerous proliferation of cells in another tissue. Because many of the genes that regulate vulval development control chromatin modifications, studies of these genes, many of which are evolutionarily conserved among species as divergent as nematodes and humans, should reveal general mechanisms involved in epigenetic inheritance, stem cell biology and such aspects of developmental biology as the determination of cell fates and differentiation. Mutants abnormal in the behavior of egg laying or in other behaviors coordinately regulated with egg laying will be identified and analyzed to establish the mechanisms used by C. elegans to modulate its behavior in response to both its environment and its experience. The focus will be on neuromodulators, specifically neuropeptides and biogenic amines. In humans, neuropeptides modulate reproduction, growth, temperature control, food intake and metabolism as well as cardiovascular, gastrointestinal and respiratory control, and the biogenic amine serotonin modulates mood, sleep and pain and is the target of the major pharmaceutical agents used to treat depression - Prozac, Paxil and Zoloft. The identification and characterization of genes that regulate neuropeptide and serotonin synthesis, release and function in the control of C. elegans egg-laying and other behaviors should reveal mechanisms that are evolutionarily conserved and that are important in many aspects of human physiology and a wide range of human behaviors and diseases. In addition, how the environment and experience modulate behavior is a fundamental and important problem in neuroscience, and these studies should establish genetic, molecular and cellular mechanisms responsible for how sensory stimuli regulate behavior and how information about past experience is stored and retrieved.